This is an application under 35 U.S.C. 371 of PCT/GB99/00585 and claims priority from Great Britain Application No. 9804885.3, filed Mar. 6, 1998.
This invention relates to the treatment or prevention of pain or nociception by the administration of a combination of a selective NMDA NR2B antagonist and an opioid analgesic.
Pain has been defined as the sensory experience perceived by nerve tissue distinct from sensations of touch, pressure, heat and cold. It is often described by sufferers by such terms as bright, dull, aching, pricking, cutting, burning, etc. This range of sensations, as well as the variation in perception of pain by different individuals, renders a precise definition of pain near impossible. Pain as suffering, however, is generally considered to include both the original sensation and the reaction to that sensation. Where pain is xe2x80x9ccausedxe2x80x9d by the stimulation of nociceptive receptors and transmitted over intact neural pathways, this is termed nociceptive pain. Alternatively, pain may be caused by damage to neural structures, often manifesting itself as neural supersensitivity, and is classed as neuropathic pain.
The level of stimulation at which pain is perceived is referred to as the xe2x80x9cpain thresholdxe2x80x9d. Where the pain threshold is raised, for instance, by the administration of an analgesic drug, a greater intensity or more prolonged stimulus is required before pain is experienced. Analgesics are a class of pharmaceutical agent which, following administration to a patient in need of such treatment, relieve pain without loss of consciousness. This is in contrast to other pain-relieving drugs, for example, general anaesthetics which obtund pain by producing a hiatus in consciousness, or local anaesthetics which block transmission in peripheral nerve fibres thereby preventing pain.
NMDA (N-methyl-D-aspartate)-type glutamate receptors are believed to play a pivotal role in the transmission of excitatory signals from primary sensory neurones to the brain through the spinal cord (A. H. Dickenson (1990) Trends Pharmacol. Sci., 11. 307-309). NMDA receptors mediate Ca2+influx into neurones, and its receptor-gated channel activity is blocked by Mg2+ in a voltage-dependant manner. Subunits of the NMDA receptors are classified into two gene families, i.e., NR1 and NR2. A variety of compounds have been designed as antagonists targeting these subunits of the NMDA receptor for the treatment of neurodegenerative disorders, as well as acute and/or chronic pain and hyperalgesia. The NR2B subunit is predominantly expressed in the hippocampus (Ishii et al., (1993), J. Biol. Chem. 268, 2836-2843).
NMDA antagonists such as ketamine, dextromethorphan and CPP are known to have analgesic properties in man. However, these agents also induce unacceptable side-effects including hallucinations. dysphoria and cognitive and motor disturbances (see Kristensen et al., 1992, Pain, 51, 249ff, Price et al., 1994, Pain, 59, 165ff and Max et al., Clin. Neuropharmacol., 118, 360ff). In preclinical studies, dextromethorphan has been reported to potentiate the antinociceptive effects of NSAIDS and morphine (Price et al.,1996, Pain, 68, 119-127; Mao et al., 1996, Pain, 67, 361-368). However, since dextromethorphan can induce adverse effects at analgesic doses in man, it is not clear from these studies whether such combinations would still be dogged with unwanted side-effects.
One selective NMDA NR2B antagonist CP-101,606 is known to possess anti-nociceptive activity, see Taniguchi et al., B. J. Pharmacol., 1997, 122, 809-812. Potent analgesic activity of this compound was shown in rat hyperalgesic and nociceptive tests at doses showing no behavioural abnormality.
There is, however, no general teaching in the art that all selective NMDA NR2B antagonists are useful as analgesics, nor that they have improved motor side-effect profile compared to NMDA/glycine antagonists. Evidence for this is, for the first time, provided herein.
Furthermore there is no suggestion in the art that selective NMDA NR2B antagonists could potentiate the effects of opioids, such as morphine, thus providing analgesia with suprisingly reduced side-effects, such as motor-impairment. Thus the safety margin for the use of opioids, such as morphine, is surprisingly improved. There is no indication in the art relating to NMDA antagonists that the property of potentiating the action of morphine could be transferred to compounds selective for the NR2B subunit.
As the present specification surprisingly demonstrates that selective NMDA NR2B antagonists possess antinociceptive effects in rat models of inflammatory and neuropathic pain with a much improved side-effect window over non-competitive NMDA antagonists (ataxic/antinociceptive), when combined with an opioid, the combination is better tolerated than expected.
The opioid analgesics are a well-established class of analgesic agent. They are also sometimes referred to as opiates although this term should be reserved for chemical relatives of morphine. The term opioid is generally accepted to refer in a generic sense to all drugs, natural or synthestic, with morphine-like actions. The synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperldines; morphinans; and benzomorphans. Pharmacologically these compounds have diverse activities, thus some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g. nalbuphine); and yet others are partial agonists (e.g. nalorphine). Whilst an opioid partial agonist such as nalorphine, (the N-alkyl analogue of morphine) will antagonise the analgesic effects of morphine, when given alone it can be a potent analgesic in its own right.
Of all of the opioid analgesics, morphine remains the most widely used and is a suitable archetype compound. Unfortunately, apart from its useful therapeutic properties, morphine also has a number of drawbacks including sedation, respiratory depression, decreased gastrointestinal motility (resulting in constipation) and, in some individuals, nausea and vomiting may occur. Another characteristic is the development of tolerance and physical dependence which mast limit the clinical use of such compounds. There is therefore a need to develop methods which enable the clinician to use lower doses of opioid analgesics such as morphine, thereby reducing the likelihood of adverse effects and development of tolerance and dependence, and thus avoiding the major problem of drug withdrawal associated with cessation of administration.